METTL16 promotes MASLD progression through the regulation of lipid synthesis and immune response.

backgroundMethyltransferase-like 16 (METTL16) is a recently identified m6A RNA methyltransferase. Although its role in hepatocellular carcinoma has been explored, its function in metabolic dysfunction-associated steatotic liver disease (MASLD) remains elusive.

methodsExpression profiles of methylation-related genes were analyzed in a cohort comprising 206 MASLD patients and 10 healthy controls. Functional assays were conducted using MASLD cell models and diet-induced mouse models. Bioinformatic analyses were performed to evaluate immune cell infiltration and signaling pathway activation. Potential transcriptional regulators and small-molecule inhibitors of METTL16 were predicted through multiple databases.

resultsMETTL16 expression was markedly upregulated in MASLD tissues and closely correlated with lipid metabolism-related pathways. Knockdown of METTL16 alleviated hepatic steatosis, insulin resistance, and fibrosis in high-fat diet-fed mice. Mechanistically, cell death-inducing DFF45-like effector family members A (CIDEA) was identified as a downstream mediator of METTL16-driven hepatic steatosis. Elevated hepatic METTL16 expression was associated with increased infiltration of innate immune cells, activation of immune-related signaling pathways, and upregulated expression of pro-fibrotic genes. Database mining further revealed that METTL16 may regulate immune-associated genes at both transcriptional and post-transcriptional levels. Additionally, EGR1 and MYC were identified as potential upstream transcriptional regulators of METTL16, and eleven small molecules were predicted to bind to and inhibit its biological activity.

conclusionMETTL16 promotes hepatic steatosis and immune-mediated fibrogenesis in MASLD. Targeting the METTL16-CIDEA axis or inhibiting METTL16 activity may serve as a promising therapeutic strategy for the treatment of MASLD.